PB2200: CLONAL HEMATOPOIESIS AT THE CROSSROADS OF INFLAMMATORY BOWEL DISEASES AND HEMATOLOGICAL MALIGNANCIES: A BIOLOGICAL LINK?
Authors: C. Cumbo, F. Tarantini, A. Zagaria, L. Anelli, C. F. Minervini, N. Coccaro, G. Tota, L. Impera, E. Parciante, M. R. Conserva, I. Redavid, P. Carluccio, M. Delia, A. Giordano, C. Longo, T. Perrone, A. Russo Rossi, G. Specchia, P. Musto, F. Albano
Journal: HemaSphere (2022)

Background: Inflammatory bowel diseases (IBDs) are a group of chronic relapsing conditions of the gastrointestinal tract. Nationwide studies have revealed a higher risk of hematological malignancies (HMs) but not colorectal cancer in IBD patients. Clonal hematopoiesis (CH) is a premalignant condition defined by the presence of an acquired somatic mutation characterized by a variant allele frequency (VAF) of ≥2% in a gene frequently associated with HMs. A growing body of evidence suggests a correlation between inflammation and CH. Aims: To assess CH possible co-occurrence in patients with an IBD associated with HMs, we performed a targeted next-generation sequencing analysis in a cohort of 13 patients who were referred to our center from February 2011 to May 2021 with IBD associated with HMs. Methods: A customized panel, encompassing 26 target genes frequently mutated in myeloid malignancies, was performed on genomic DNA from bone marrow (BM) (cases #3 - #13) or peripheral blood (cases #1, #2) samples. Only variants (non-intronic, non-synonymous, with >1% global MAF in the healthy population) affecting the CH-associated genes, with ≥2% VAF, and with a depth of coverage >500x were considered. Results: Overall, 20 variants affecting 9 genes (DNMT3A, ASXL1, JAK2, GATA2, TET2, ETV6, SF3B1, EZH2, KIT) were detected in our cohort; 11/13 (85%) patients showed one or more mutations, with a VAF ranging from 2.6% to 53.0%. Moreover, cases #6 and #7 showed variants of CH-associated genes but in the absence of a BM lymphoma localization. Five variants (25.0%) showed a VAF<10%, whereas, in the 15 others identified (75.0%), the clone was dominant. In accordance with previously published data in the IBD context, DNMT3A was the most frequently mutated gene (4/20, 20.0%) (13,14), with ASXL1 (4/20, 20.0%), followed by JAK2 (3/20, 15.0%). All mutations are single nucleotide variants (SNV) with different functions: missense variants (13/20, 65.0%), nonsense variants (4/20, 20.0%), and unknown variants affecting a splice site or an untranslated region (3/20, 15.0%). Five cases (45.5%) carried just one variant, whereas the other six (54.5%) showed two or more mutations. Recent works demonstrated that chronic infection, ulcerative colitis (UC) and atherosclerosis, can drive the gene loss of function associated with CH. In particular, chronic infection and UC may promote the selection of the DNMT3A gene mutation associated with CH by the IFNγ signaling induced in the course of these disorders. It is worthy of note that four (36.4%) cases in our series bore DNMT3A gene mutations. According to data previously shown in UC patients, this fact may be considered to demonstrate that the mechanisms at the basis of the inflammatory environment potentially select for the growth of CH specific mutations. Thus, CH as a possible biological link, may be fed by the IBD inflammatory stimuli, and in turn, feed the IBD inflammation. Particularly, the low VAF of DNMT3A gene in cases #6 and #7, both patients without evidence of BM lymphoma involvement, is strongly suggestive of CH promoted by IBD. Furthermore, cases #1, #2, #8, #10, #11 showed CH-associated gene variants usually rare in chronic myeloid and lymphoid leukemia. Summary/Conclusion: Our report suggests that CH may be seen as a biological link at the crossroads of IBDs and HMs, whose role is yet to be fully elucidated. Nonetheless, if these data are confirmed, IBD patients screened and positive for CH should undergo hematologic follow-up to assess the risk of developing HM. Further studies are warranted to characterize the biological relationship between IBDs, CH, and HMs.